WO2023042126A1 - Procédé de préparation de 5-fluoro-4-imino-3-méthyl-1-(toluène-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one - Google Patents
Procédé de préparation de 5-fluoro-4-imino-3-méthyl-1-(toluène-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one Download PDFInfo
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- WO2023042126A1 WO2023042126A1 PCT/IB2022/058732 IB2022058732W WO2023042126A1 WO 2023042126 A1 WO2023042126 A1 WO 2023042126A1 IB 2022058732 W IB2022058732 W IB 2022058732W WO 2023042126 A1 WO2023042126 A1 WO 2023042126A1
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- 238000004519 manufacturing process Methods 0.000 title description 12
- KVUHRPLZWABERU-UHFFFAOYSA-N 5-fluoro-4-imino-3-methyl-1-(4-methylphenyl)sulfonylpyrimidin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)N(C)C(=N)C(F)=C1 KVUHRPLZWABERU-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 684
- 238000000034 method Methods 0.000 claims abstract description 178
- 239000012296 anti-solvent Substances 0.000 claims abstract description 38
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical class COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 341
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 267
- 239000000203 mixture Substances 0.000 claims description 258
- 238000006243 chemical reaction Methods 0.000 claims description 195
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 190
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 148
- 239000011541 reaction mixture Substances 0.000 claims description 145
- 239000003637 basic solution Substances 0.000 claims description 138
- 239000007787 solid Substances 0.000 claims description 131
- 239000002585 base Substances 0.000 claims description 120
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 114
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 109
- 239000002798 polar solvent Substances 0.000 claims description 108
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 94
- 239000012074 organic phase Substances 0.000 claims description 88
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 78
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 74
- 238000001914 filtration Methods 0.000 claims description 71
- 239000012071 phase Substances 0.000 claims description 71
- 239000002002 slurry Substances 0.000 claims description 62
- 239000000243 solution Substances 0.000 claims description 56
- 238000005406 washing Methods 0.000 claims description 48
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 47
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 44
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 39
- 150000003839 salts Chemical group 0.000 claims description 38
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 38
- 239000007864 aqueous solution Substances 0.000 claims description 32
- 235000015320 potassium carbonate Nutrition 0.000 claims description 29
- 239000011736 potassium bicarbonate Substances 0.000 claims description 28
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 28
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 239000012973 diazabicyclooctane Substances 0.000 claims description 19
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 18
- -1 EtsN Chemical compound 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000002253 acid Chemical group 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
- 150000002148 esters Chemical group 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 8
- 239000003586 protic polar solvent Substances 0.000 claims description 8
- 125000003944 tolyl group Chemical group 0.000 claims description 8
- 238000010899 nucleation Methods 0.000 claims description 6
- 239000003849 aromatic solvent Substances 0.000 claims description 5
- 239000004210 ether based solvent Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 128
- 229940113088 dimethylacetamide Drugs 0.000 description 128
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 122
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 238000002955 isolation Methods 0.000 description 22
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 21
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000003960 organic solvent Substances 0.000 description 16
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000012535 impurity Substances 0.000 description 13
- 238000005804 alkylation reaction Methods 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 9
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 239000012454 non-polar solvent Substances 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 6
- 238000005191 phase separation Methods 0.000 description 6
- 239000003444 phase transfer catalyst Substances 0.000 description 6
- 239000011369 resultant mixture Substances 0.000 description 6
- 238000006277 sulfonation reaction Methods 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000007070 tosylation reaction Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- IGEAUAWXDNMZMF-UHFFFAOYSA-N 4-amino-5-fluoro-1-(4-methylphenyl)sulfonylpyrimidin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)N=C(N)C(F)=C1 IGEAUAWXDNMZMF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XUEZMHGLLYOBIT-UHFFFAOYSA-N phenylmethanamine;hydrate Chemical compound [OH-].[NH3+]CC1=CC=CC=C1 XUEZMHGLLYOBIT-UHFFFAOYSA-N 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 3
- 241001436679 Adama Species 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011833 salt mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GNWBLLYJQXKPIP-ZOGIJGBBSA-N (1s,3as,3bs,5ar,9ar,9bs,11as)-n,n-diethyl-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1h-indeno[5,4-f]quinoline-1-carboxamide Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(CC)CC)[C@@]2(C)CC1 GNWBLLYJQXKPIP-ZOGIJGBBSA-N 0.000 description 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- QGKGASXQTBQINX-UHFFFAOYSA-N 3,4-dihydro-1h-pyrimidin-2-one Chemical compound O=C1NCC=CN1 QGKGASXQTBQINX-UHFFFAOYSA-N 0.000 description 1
- ZYNWCIYUVDFAJI-UHFFFAOYSA-N CN1CN(C=C(F)C1=N)S(=O)(=O)c1ccc(C)cc1 Chemical compound CN1CN(C=C(F)C1=N)S(=O)(=O)c1ccc(C)cc1 ZYNWCIYUVDFAJI-UHFFFAOYSA-N 0.000 description 1
- 241001251223 Septaria Species 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- UATOFRZSCHRPBG-UHFFFAOYSA-N acetamide;hydrate Chemical compound O.CC(N)=O UATOFRZSCHRPBG-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000012677 causal agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Definitions
- the present subj ect matter relates to an efficient procedure for obtaining 5-f luoro-4-imino-3-methyl-l- (toluene-4-sulf onyl ) -3 , 4- dihydro-lH-pyrimidin-2 -one .
- 5-f luoro- 4 -imino -3 -methyl -1- ( toluene -4 -sulf onyl ) -3 , 4 -dihydro- 1H- pyrimidin-2 -one is a systemic fungicide which provides control of variety of pathogens in economically important crops including , but not limited to , the causal agent of leaf blotch in wheat, Septaria tri ti ci ( SEPTTR) .
- the present invention provides a process for obtaining 5-fluoro-4- imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2- one having formula (I) : comprising :
- DMS dimethylsulphate
- R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF 3 , and
- step (1) is conducted in the presence of at least one water-immiscible solvent, and/or ii) at least one water-immiscible solvent is added to the reaction mixture after step (1) .
- the present invention also provides a method for isolating a compound having formula (I) from a mixture comprising the compound having formula (I) , wherein the method comprises (i) preparing a multi-phase system comprising the compound having formula (I) , a water-immiscible solvent and water, and (ii) obtaining and isolating solids of the compound having formula (I) from the multiphase system.
- the present invention also provides a monomethylsulfate salt of the compound having formula (I) .
- the present invention also provides a method for crystallizing or recrystallizing a compound having formula (I) , comprising (i) preparing a solution comprising a compound having formula (I) and a solvent, and (ii) contacting the solution with an anti-solvent.
- the present invention also provides use of an anti-solvent to crystalize or recrystallize a compound having formula (I) from a solution thereof.
- the present invention also provides a method for isolating a compound having formula (II) from a mixture comprising the compound having formula (II) , wherein the method comprises (i) adding a protic solvent to the mixture to precipitate the compound having formula (II) from the mixture, and (ii) collecting the precipitated compound of formula (II) .
- use of the term "about” herein specifically includes ⁇ 10% from the indicated values in the range. By way of example, about 15% therefore includes 13.5%, 13.6%, 13.7%, etc. up to 16.5%. Use of the term “about” herein more specifically includes ⁇ 1% from the indicated values in the range. By way of example, about 100 mg/kg therefore includes 99, 99.1, 99.2, 99.3, 99.4,
- about 100 mg/kg includes, in an embodiment, 100 mg/kg.
- endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges.
- a range is given in the specification it is understood that the range includes all integers and 0.1 units within that range, and any sub-range thereof.
- a range of "2-18%" is a disclosure of 2.0 %, 2.1 %, 2.2 %, 2.3% etc. up to 18%.
- alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- Ci-C n as in “Ci-C n alkyl” is defined to include groups having 1, 2 , n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
- An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on.
- An embodiment can be Ci-Cs alkyl, C 2 -Ca alkyl, C3-C8 alkyl, C4-C8 alkyl and so on.
- alkoxy represents an alkyl group as described above attached through an oxygen bridge.
- Ph is referring to phenyl group.
- soluble means when 1g of substance is dissolved in the approximate volume of 100 ml.
- water immiscible when used in relation to a solvent means that the solvent does not completely mix with water to form a one phase solution.
- polar solvent refers to solvent which has a dielectric constant equal to or above 20.
- polar solvent has the meaning commonly understood by one of skill in the art to which this subject matter pertains, and includes, but is not limited to, solvent which has a dielectric constant equal to or above 20.
- the polar solvent used in each of the sulfonation step, the alkylation step and isolation step may be the same or different.
- the polar solvent has a dielectric constant equal to or above 20.
- formula (II) refers to the following structure : wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF 2 , and tautomers thereof, including but not limited to enamine tautomers thereof.
- Formula (Ilai) refers to the following structure : tautomers thereof, including but not limited to an enamine tautomer thereof.
- the compound having formula (Ilai) includes both of the following compounds:
- the present invention provides a process for obtaining 5-fluoro-4- imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2- one having formula (I) : comprising :
- DMS dimethylsulphate
- R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF 3 , and
- step (1) is conducted in the presence of at least one water-immiscible solvent, and/or ii) at least one water-immiscible solvent is added to the reaction mixture after step (1) .
- R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF3.
- the compound having the formula (II) is (Ila) wherein R is alkyl.
- the compound having the formula (Ila) is (Ilai) wherein R is methyl.
- the compound having the formula (I) is (la) wherein R is alkyl.
- the compound having the formula (la) is (lai) wherein R is methyl.
- the process forms a multi-phase system.
- a multi-phase system is obtained at the end of step 2, .
- the multi-phase system comprises an organic phase and a water phase.
- the multi-phase system is a slurry mixture comprising solids. The type of multiphase system formed depends on the volume of the water-immiscible solvent and/or the temperature.
- the organic phase comprises the water-immiscible solvent.
- the process comprises heating the multi-phase system for dissolution of the compound having formula (I) in the organic phase. In some embodiments, the process comprises heating the multi-phase system up to 80°C for dissolution of the compound having formula (I) in the organic phase.
- the process for isolating the compound having formula (I) from the reaction mixture comprises separating the organic phase from the water phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals.
- the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 2.
- step (1) is conducted in the presence of at least one water-immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS and at least one water immiscible solvent.
- the water immiscible solvent is added after step (1) and before step (2) and the reaction mixture comprises the compound having formula (I) , DMS and at least one water immiscible solvent.
- step (2) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the organic phase and filtering the crystals.
- DMS dimethylsulphate
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the reaction mixture and filtering the crystallized solid, or
- DMS dimethylsulphate
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO3, Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO3, Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH 4 OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO3.
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w/w) .
- the compound having the formula (I) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.
- the compound having the formula (I) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.
- the water immiscible solvent is polar. In some embodiments, the water immiscible solvent is non-polar. In some embodiments, the water immiscible solvent is an organic polar solvent .
- the water immiscible solvent includes but not limited to cyclopentylmethylether (CPME) , methyl tetrahydrofuran (MeTHF) , DCM, toluene, anisole or any combination thereof.
- CPME cyclopentylmethylether
- MeTHF methyl tetrahydrofuran
- DCM toluene
- anisole anisole
- the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof.
- the water immiscible solvent is selected from the group consisting of MeTHF, CPME, toluene, anisole, and any mixture thereof.
- the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.
- the compound having the formula (I) is crystallized from the organic phase by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by adding an anti-solvent. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by seeding.
- the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane.
- the compound having formula (I) in the mixture is in salt form.
- the process for isolating the compound having formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w/w of aqueous basic solution, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid.
- the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w/w of aqueous basic solution, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid .
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.
- the organic polar solvent is an organic polar water immiscible solvent.
- the organic water immiscible solvent has a dielectric constant less than 20.
- organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.
- MeTHF methyl tetrahydrofuran
- CPME cyclopentylmethylether
- the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM and any combination thereof.
- the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .
- the organic polar solvent is DMA.
- the organic polar solvent is CPME.
- the organic polar solvent is MeTHF.
- the compound having formula (I) is a compound having formula (la) wherein R is alkyl.
- the compound having formula (la) is a compound having formula (lai) wherein R is methyl.
- the organic phase is cooled prior to and/or during the filtration. In some embodiments, the organic phase is cooled to 0-5°C.
- the organic polar solvent is added after the reaction to obtain the compound having the formula (I) .
- the CPME is added after the reaction to obtain the compound having the formula (I) .
- a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) .
- a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .
- the compound having the formula (I) in the mixture before the isolation step is in salt form.
- the non-polar solvent is a non-polar water immiscible solvent.
- the non-polar water immiscible solvent dissolves the compound of formula (I) .
- the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.
- the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.
- an anti-solvent is further added.
- the anti-solvent is added parallel to the to the water immiscible solvent.
- the anti-solvent is added dropwise.
- the crystallization is conducted at temperature less than 0°C.
- the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane.
- the mixture of solvent and anti-solvent are anisole and hexane.
- the mixture of solvent and anti-solvent are toluene and hexane
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the compound having formula (I) is a compound having formula (la) wherein R is alkyl.
- the compound having formula (la) is a compound having formula (lai) wherein R is methyl.
- the organic phase is cooled prior to and/or during the filtration. In some embodiments, the organic phase is cooled to 0-5°C.
- the crystallization is done by concentration of the solvent.
- the crystallization is done with crystal seeding .
- the mixture is seeded with 0.1-1% of the compound of formula (I) .
- the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) .
- anisole and hexane are added after the reaction to obtain the compound having the formula (I) .
- a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) .
- a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •
- the process for isolating the compound having formula (I) comprises contacting the mixture comprising the compound having formula (I) with a water-immiscible solvent or a mixture of solvents comprising at least one water immiscible solvent and water, separating the organic phase, crystalizing the compound having the formula (I) , and (3)filtering the crystals.
- the process for isolating the compound having formula (I) form the reaction mixture comprises filtering the precipitated solids.
- the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 3.
- step (1) is conducted in the presence of at least one water-immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent
- step (2) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids .
- the water immiscible solvent is added after step (1) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent
- step (2) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- step (1) is conducted in the presence of at least one additional solvent.
- step (1) is conducted in the presence of at least one additional solvent
- step (1) is conducted in the presence of at least one water-immiscible solvent and
- the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent
- step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- step (1) wherein (a) step (1) is conducted in the presence of at least one additional solvent, (b) the water immiscible solvent is added after step (1) , and (c) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- At least one additional solvent is added after step (1) and before step (2) .
- step (1) is conducted in the presence of at least one water-immiscible solvent and (c) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent
- step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids , and (ii) filtering the precipitated solids.
- step (2) is conducted in the presence of at least one additional solvent.
- step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- step (2) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids.
- DMS dimethylsulphate
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .
- DMS dimethylsulphate
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.
- DMS dimethylsulphate
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .
- DMS dimethylsulphate
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH 4 OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) .
- the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w/w) .
- the compound having the formula (I) in the mixture is in salt form.
- the mixture comprises a solvent. In some embodiments, the slurry mixture comprises a solvent.
- the mixture comprising the compound having formula (I) may comprise DMS and any or all solvents used during the process for preparing the compound having formula (I) .
- the additional solvent is a solvent used to isolate or assist in the isolation of the compound having formula (I) .
- the additional solvent may be added directly to the mixture.
- the additional solvent may also be added with the aqueous basic solution.
- the additional solvent is the same as the solvent (s) used during the process for preparing the compound having formula (I) .
- the additional solvent is different from the solvent (s) used during the process for preparing the compound having formula (I) .
- the additional solvent is a polar solvent.
- the additional solvent is a water immiscible solvent
- the polar solvent has a dielectric constant equal to or above 4. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.
- the ratio between the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is about 1:1.
- the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.
- the additional solvent is a polar solvent and the polar solvent is CPME.
- the solvent used during the process for preparing the compound having formula (I) is DMA and the additional solvent is CPME.
- the ratio between CPME to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (I) is about 1:1.
- the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.
- the slurry mixture is mixed for 30 minutes to
- the slurry mixture is mixed at temperature between 25 to 60 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 50 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 35 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 30 degrees Celsius.
- the slurry mixture is mixed using mechanical stirrer .
- the slurry mixture is mixed using high shear stirrer .
- the slurry mixture is mixed using both mechanical stirrer and high shear stirrer.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution.
- the precipitated solids are filtered at a temperature between 15 to 45 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 15 to 20 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 20 to 25 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 25 to 30 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 30 to 35 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 35 to 40 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 40 to 45 degrees Celsius.
- the filtered solid obtained in step (2) is washed with an organic solvent during filtration in step (2) .
- the organic solvent is CPME.
- the filtered solid obtained in step (2) is washed with water during filtration in step (2) .
- the filtered solid is mixed with water and stirred for 1 to 3 hours and filtered.
- the filtered solid is mixed with water and stirred at a temperature of 25-50 degrees Celsius and filtered.
- the organic solvent is the same organic solvent as used in obtaining the compound having formula (I) •
- the aqueous basic solution is 15% of K2CO3 in water based on the total weight (w/w) of K2CO3 in water.
- the organic phase is the solution which is obtained in the reaction of compound having the formula (II) with
- the organic phase is obtained by adding an organic water immiscible solvent to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.
- the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) .
- PTC phase transfer catalyst
- TBAB tetra-n-butylammonium bromide
- a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) in weight ratio of 10:1 prior to washing with 2-18% w/w of aqueous basic solution.
- the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to 65°C prior to washing with 2-18% w/w of aqueous basic solution.
- the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to about 50°C prior to washing with 2-18% w/w of aqueous basic solution.
- the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved in CPME.
- the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved with CPME and washed with water base solution.
- the resultant mixture is a mixture of the compound having formula (I) with the solvent which was used in the reaction of the compound having formula (II) with DMS.
- the chemical yield of 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%.
- the yield of the purified 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.
- the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one to 5-fluoro- 4 -imino -3 -methyl -1- (phenyl- 4 -sulf onyl ) -3 , 4 -di hydro- IH-pyrimi di n- 2-one is higher than 50%.
- the chemical yield of 5-f luoro-4-imino-3- methyl-1- (phenyl-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%.
- the yield of the purified 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.
- the mixture comprises the compound having formula (I) , at least one water immiscible solvent, and at least one additional solvent
- the process for isolating the compound having formula (I) comprises (i) washing the mixture with water to obtain slurry mixture containing solids, and (ii) filtering the precipitated solids.
- the multi-phase system comprises a liquid and solids. In some embodiments, wherein the multi-phase system comprises a liquid and solids, the process for isolating the compound having formula (I) from the reaction mixture comprises filtering the solids.
- the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 1.
- the mixture comprises the compound having formula (I) and DMS
- the process for isolating the compound having formula (I) from the reaction mixture comprises (1) adding at least one water immiscible solvent and an aqueous basic solution to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids.
- the compound having formula (I) in the mixture is in salt form.
- the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is polar.
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.
- the polar solvent is an organic polar solvent.
- the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.
- the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM and any combination thereof.
- the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.
- the process comprises evaporation of the polar solvent prior to filtration. In some embodiments, the process comprises partial evaporation of the polar solvent prior to filtration . In some embodiments, the process comprises cooling the reaction mixture prior to filtration.
- step (1) is conducted in the presence of at least one water-immiscible solvent.
- the water immiscible solvent is added after step (1) and before addition of the aqueous basic solution to the reaction mixture.
- the water immiscible solvent is added at the same time as addition of the aqueous basic solution to the reaction mixture .
- the water immiscible solvent is added after addition of the aqueous basic solution to the reaction mixture. In some embodiments, the water immiscible solvent is added immediately after addition of the aqueous basic solution to the reaction mixture .
- the water immiscible solvent is an ether-based solvent, an aromatic solvent, or a mixture thereof.
- the water immiscible solvent is CPME, THE, anisole, toluene, or any mixture thereof.
- the water-immiscible solvent is toluene, anisole, or a combination thereof.
- the water immiscible solvent and the aqueous basic solution are added sequentially.
- the water immiscible solvent is added gradually .
- step (1) is conducted in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.
- step (1) is conducted in the presence of at least one water-immiscible solvent.
- the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.
- the water-immiscible solvent is toluene, anisole, or a combination thereof.
- step (1) is conducted in the presence of a solvent in addition to the water immiscible solvent.
- step (1) is conducted in the presence of a solvent and without a water immiscible solvent.
- the solvent is DMA.
- step (1) is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.
- the mixture of solvents is a mixture of a polar water miscible solvent and a non-polar water-immiscible solvent .
- the mixture of solvents is DMA and anisole. In some embodiments, the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1. In some embodiments, the mixture of solvents is a mixture of DMA and toluene. In some embodiments, the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1.
- the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.
- the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) .
- the compound having formula (I) may be in salt form.
- the compound having formula (I) is in salt form.
- the compound having the formula (I) is in salt form during the reaction.
- the compound having formula (I) is partially in salt form.
- the compound having formula (I) is partially in salt form during the reaction.
- the salt of the compound having formula (I) is a monomethylsulfate salt of the compound having formula ( I ) .
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystalized solid.
- step (i) comprises washing the reaction mixture with 2-18% w/w of aqueous basic solution to form an organic phase and a water phase .
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.
- DMS dimethylsulphate
- step (i) comprises washing the reaction mixture with 2-18% w/w of aqueous basic solution to form an organic phase and a water phase .
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent and an aqueous basic solution to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.
- DMS dimethylsulphate
- the aqueous basic solution is a 2-18% w/w aqueous basic solution.
- the compound having the formula (I) is crystalized by concentrating the organic phase, adding an antisolvent, and/or seeding.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids.
- DMS dimethylsulphate
- step (i) comprises washing the reaction mixture with 2-18% w/w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .
- DMS dimethylsulphate
- step (i) comprises washing the reaction mixture with 2-18% w/w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.
- step (i) comprises washing the reaction mixture with 2-18% w/w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.
- the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .
- DMS dimethylsulphate
- the aqueous basic solution is a 2-18% w/w aqueous basic solution.
- the aqueous basic solution is an aqueous solution comprising DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt, or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH4OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w/w) .
- the additional solvent is different from the water immiscible solvent.
- the additional solvent is a polar solvent.
- the polar solvent has a dielectric constant equal to or above 5.
- the ratio between the additional solvent to the compound having formula (I) or formula (II) is about 1:1.
- the additional solvent is CPME.
- the slurry mixture is mixed at a temperature between 25 to 50 degrees Celsius.
- step (2) the precipitated solids are filtered at a temperature between 15 to 45 degrees Celsius.
- the water immiscible solvent is polar.
- the water immiscible solvent is non-polar.
- reaction of the compound having formula (II) with DMS is conducted in the absence of base.
- reaction of the compound having formula (II) with DMS is conducted in the presence of at least one base.
- the base is selected from the group consisting of DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the base is selected from the group consisting of TBAB, NaOH, Na 2 CO 3 , Et 3 N, NaOMe, and any combination thereof.
- the compound having formula (I) when a base is present in the reaction of the compound having formula (II) with DMS, and the base has a pKa that is higher than the pKa of the compound having formula (I) , the compound having formula (I) is not in salt form.
- the reaction of the compound having formula (II) with DMS is conducted at a temperature between 25-85 °C. In some embodiments, the temperature is between 25-50 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 35-50 °C.
- the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:4. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3.5.
- the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:5.5.
- the base is added after 4 hours from the beginning of the reaction of compound (II) with DMS .
- Suitable bases include alkoxides and carbonates.
- the base is added after 4 hours from the beginning of the reaction of the compound having formula (II) with DMS and the temperature of the reaction is above 30 degrees Celsius.
- the base is added at the beginning of the reaction.
- Suitable bases include DABCO, NEts, LiCOs, and KHCO3.
- the temperature is preferably above 30 degrees Celsius.
- reaction of the compound having formula (II) with DMS is conducted in the presence of at least one solvent. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of two solvents.
- reaction of the compound having formula (II) with DMS is conducted in the presence of one solvent and the solvent is water immiscible.
- the reaction of the compound having formula (II) with DMS is conducted in the presence of two or more solvents and at least one of the solvents is water immiscible.
- the other solvent (s) may be water immiscible or water miscible.
- the solvent is a polar solvent. In some embodiments, the solvent is a non-polar solvent.
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.
- the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole and any combination thereof.
- the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM and any combination thereof .
- the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is toluene. In some embodiments, the solvent is anisole.
- the solvent (s) is a solvent that dissolves the compound of formula (I) completely.
- the solvent is MeTHF and the base is NEts .
- the solvent is a mixture of at least two solvents .
- the solvent is a mixture of DMA and CPME.
- the weight ratio between DMA and CPME is between 1:1 to 1:10. In some embodiments, the weight ratio between DMA and CPME is between 1:1 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:2 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:3 to 1:5. In some embodiments, the weight ratio between DMA and CPME is about 1:4.
- the solvent is a mixture of DMA and MeTHF.
- the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:1 to 1:4. In some embodiments, the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:2 to 1:4.
- the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:2 to 1:4. In some embodiments, the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:4.
- the solvent is a mixture of a polar water- miscible solvent and a non-polar water-immiscible solvent.
- the solvent is a mixture of DMA and anisole.
- the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is between 75:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is between 50:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is between 25:1 to 1:1. In some embodiments, the weight ratio between
- DMA and anisole is about 1:1.
- the solvent is a mixture of DMA and toluene.
- the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is between 75:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is between 50:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is between 25:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1.
- the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 30:1 and 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 20:1 and 5:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 15:1 and 10:1.
- the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 14:1 to 12:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is about 13:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is 12.7:1.
- the molar ratio between the solvent or mixture of solvents to DMS is between 10:1 to 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is between 5:1 to 3:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is about 4:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is 3.9:1.
- reaction of the compound having formula (II) with DMS further comprises neutralizing with an aqueous basic solution .
- the excess DMS is neutralized with an aqueous basic solution.
- the weight ratio of the DMA: CPME : compound having the formula (II) is 1.5:0:l to 1:5:1.
- the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1.
- the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.
- the base in the aqueous basic solution may include but is not limited to K2CO3, KHCO3, Na 2 CO3, NaHCOs, K2CO3 NH4OH, NaOH or any combination thereof.
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) .
- the base in the aqueous basic solution is K2CO3.
- the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) .
- PTC phase transfer catalyst
- TBAB tetra-n-butylammonium bromide
- the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 60%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 70%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 80%.
- the compound having formula (II) may be prepared using any process known in the art including, but not limited to, the process described in PCT International Application Publication Nos. WO 2015/103142 and WO 2015/103144, the entire content of each of which is hereby incorporated by reference.
- the compound having formula (Ilai) is prepared by contacting a compound having formula (IV) : with bis-N, O-trimethylsilylacetamide (BSA) and forming a compound having formula (Ilai) , wherein the molar ratio of the compound having formula (IV) to bis- N, O-trimethylsilylacetamide (BSA) is 1:1.1 and the contacting step is carried out at a temperature from about 22 °C to about 70 °C.
- the contacting step further includes contacting the compound having formula (IV) with CH3CN.
- the process comprises contacting a BSA treated reaction mixture with an arylsulfonyl chloride.
- the molar ratio between the compound having formula (IV) to arylsulfonyl chloride is from about 1:2 to about 2:1. In some embodiments, the molar ratio between the compound having formula (IV) to arylsulfonyl chloride 1:1.1.
- the compound having formula (Ilai) may be prepared by contacting a compound having formula (IV) with bis- N, O-trimethylsilylacetamide (BSA) at an elevated temperature, such as 70°C, for a period of about 1 hour (h) , followed by cooling and contacting the solution containing the protected pyrimidinol with CH3-PhSO 2 Cl at about 20°C - 25°C.
- BSA bis- N, O-trimethylsilylacetamide
- the molar ratio between the compound having formula (IV) to BSA and the sulfonyl chloride is about 1:3: 1.1, respectively.
- reducing the molar ratio of the reactants to about 1:1.1:1.1 affords improved yields.
- the compound having formula (II) may be prepared using the process described in PCT International Application Publication No. WO/2021/181274, the entire content of which is hereby incorporated by reference.
- the compound having formula (II) is prepared by reacting 5-f luorocytosine with compound having the formula (HI) : in the presence of at least one polar solvent and at least one base, wherein:
- R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF3; and
- X is a halogen or -OSO 2 PhR.
- the compound having the formula (II) is (Ila) wherein R is alkyl.
- the compound having formula (II) is a compound having formula (Ilai)
- the present invention also provides a process for obtaining the compound 5-f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4- dihydro-lH-pyrimidin-2-one having formula (I) : comprising :
- R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF3.
- the compound having the formula (I) is (la) wherein R is alkyl. In some embodiments, the compound having the formula (la) is (lai) wherein R is methyl.
- the compound having formula (I) is a compound having formula (lai) : and the process comprises:
- the compound having formula (I) may be in salt form. Water may be added in the form of an aqueous basic solution.
- the compound having formula (I) is in salt form.
- the compound having the formula (I) is in salt form during the reaction.
- the compound having formula (I) is partially in salt form.
- the compound having formula (I) is partially in salt form during the reaction.
- the salt of the compound having formula (I) is a monomethylsulfate salt of the compound having formula ( I ) .
- a salt or salt mixture is optionally added to a reaction mixture after DMS is added to the reaction.
- the salt or the salt mixture is prepared in a previous alkylation reaction.
- the compound having the formula (I) obtained in the alkylation is suspended in the solvent. In some embodiments, the compound having the formula (I) obtained in the alkylation is soluble in the solvent. In some embodiments, the salt of the compound having the formula (I) is suspended in the solvent. In some embodiments, the salt of the compound having the formula (I) is soluble in the solvent. In some embodiments, the salt or salt solution is added to alkylation reaction after the addition of dimethylsulfate .
- the present invention provides a monomethylsulfate salt of the compound having formula (I) .
- the reaction of 5-f luorocytosine with the compound having formula (III) is carried out in the absence of protecting group.
- X is a halogen.
- the halogen is Cl, Br or I.
- the halogen is Cl.
- X is -OSO 2 PhR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF 3 .
- R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 ,
- the compound having formula (III) is a compound having formula (Illb) wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF 3 .
- X is -OSO 2 PhR and R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF3.
- R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH 2 , -NO 2 , -CN or CF3.
- R is alkyl
- the compound having formula (III) is toluenesulfonyl anhydride.
- the compound having the formula (III) may include but is not limited to 4-toluenesulf onyl chloride (TsCl) and toluenesulfonyl anhydride.
- the compound having the formula (III) is 4- toluenesulf onyl chloride (TsCl) . In some embodiments, the compound having the formula (III) is toluenesulfonyl anhydride.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at a temperature between (-5)- 85°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-25°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-5°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)- 0°C.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 0-5 °C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between 5-25 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 25-85°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent and at least one base.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base and at a temperature between 0-5 °C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents, one base and at a temperature between 0-5 °C.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base and at a temperature between 5-25°C.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a polar solvent, at least one base and at a temperature between 25-85°C.
- reaction of 5-f luorocytosine with compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base and at a temperature between (-5) -85°C.
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.
- the sulfonation step is a tosylation step.
- the polar solvent has a dielectric constant equal to or above 20 .
- the polar solvent having dielectric constant equal to or above 20 may include but is not limited to dimethyl acetamide (DMA) , N-methylpyrolidone (NMP ) , acetonitrile (ACN or MeCN) , dimethylsulfoxide (DMSO) , dimethylformamide ( DMF) , water or any combination thereof .
- DMA dimethyl acetamide
- NMP N-methylpyrolidone
- ACN or MeCN acetonitrile
- DMSO dimethylsulfoxide
- DMF dimethylformamide
- the polar solvent is selected from the group consisting of dimethyl acetamide ( DMA) , N-methylpyrolidone (NMP ) , acetonitrile (ACN or MeCN) , dimethylsulfoxide ( DMSO) , dimethylformamide ( DMF) , dimethylbenzylamine ( DMBA) , water and any combination thereof .
- DMA dimethyl acetamide
- NMP N-methylpyrolidone
- ACN or MeCN acetonitrile
- DMSO dimethylsulfoxide
- DMF dimethylformamide
- DMBA dimethylbenzylamine
- the polar solvent is selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethylbenzylamine (DMBA) , water and any combination thereof .
- DMA dimethyl acetamide
- ACN or MeCN acetonitrile
- DMBA dimethylbenzylamine
- the combination of polar solvent and base consist of one phase system .
- reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of one polar solvent .
- reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of two polar solvents .
- the two polar solvents are selected from the group consisting of dimethyl acetamide ( DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsulfoxide ( DMSO) , dimethylformamide (DMF) , dimethylbenzylamine ( DMBA) , and water .
- the two polar solvent are selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethyl aminopyridine (DMAP) , and water.
- the two polar solvents are DMA and water.
- the weight ratio between the two polar solvents is between 10:1 to 1:10.
- the weight ratio between the two polar solvents is between 2:1 to 1:2.
- the weight ratio between the two polar solvents is 1:1.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of three polar solvents .
- the three polar solvents are DMA, water and DMBA.
- At least one base is an organic base.
- At least one base is an inorganic base.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of one base.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two bases .
- the base may include but is not limited to K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, Et 3 N, dimethyl aminopyridine (DMAP) , dimethylbenzylamine (DMBA) or any combination thereof.
- the base is selected from a group consisting of K2CO3, Na 2 CO3, Li 2 CO3, NaHCOs, KHCO3, Et 2 N, dimethyl aminopyridine (DMAP) and any combination thereof.
- the base is selected from the group consisting of K 2 CO3, Na 2 CO3, NaOH, KOH, Et 2 N, dimethyl aminopyridine (DMAP) , and any combination thereof.
- the base is K 2 CO3. In some embodiments, the base is Na 2 CO3. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is Et 2 N. In some embodiments, the base is DMAP.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA and at least one base.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water and at least one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water and one base.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water and two bases.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA and two bases.
- the two bases are Et 2 N and DMAP .
- the two bases are NaOH and DMAP.
- the two bases are dimethylbenzylamine and
- the two bases are DMAP and Na 2 CO 3 .
- the two bases are DMAP and KOH.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA, water and K 2 CO 3 .
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA and Et 3 N.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of acetonitrile (ACN or MeCN) and triethylamine (Et 3 N) .
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA, water and DMAP.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA and Na 2 CO 3 .
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMBA and Na 2 CO 3 .
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of water and DMAP.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMBA, DMA, water and KOH. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMBA, DMA, water and NaOH.
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, Et 3 N and DMAP .
- the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, NaOH and DMAP.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMAP and Na 2 CO 3 .
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMBA and KOH.
- reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMBA and NaOH.
- the polar solvent has a dielectric constant equal to or above 20 is DMA, and the base is Et 3 N.
- the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water, and the base is K 2 CO 3 .
- the polar solvent has a dielectric constant equal to or above 20 is water, the base is Et 3 N and the temperature is (-5) -5°C.
- the temperature is (-5)-5°C, and the solvent is acetonitrile. In another preferred embodiment, the temperature is (-5)-5°C, the solvent is acetonitrile, and the base is EtsN.
- the molar ratio between 5- f luorocytosine and the compound having formula (III) is between 1:10 to 10:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:2 to 2:1.
- the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1.1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is 1:1.2.
- the molar ratio between 5- f luorocytosine and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:2 to 2:1.
- the molar ratio between 5- f luorocytosine and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is about 1:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.3.
- the molar ratio between the compound having formula (III) and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:2 to 2:1.
- the molar ratio between the compound having formula (III) and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is 1:1.2.
- the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield of at least 61%.
- the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 60%, 70%, 80%, 90% or 99%. In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 90%.
- the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 20% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 10% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 5% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 3% based on the conversion.
- the reaction of 5-f luorocytosine with the compound having formula (III) to obtain compound having the formula (II) further comprises a step of isolating the compound having formula (II) from the reaction mixture.
- isolation of the compound having formula (II) comprises (i) adding a protic solvent to the reaction mixture to precipitate the compound having formula (II) from the reaction mixture, and (ii) collecting the precipitated compound of formula (ID •
- the protic solvent is water, methanol or a combination thereof.
- the present invention also provides a compound having formula (II) prepared using the process described herein.
- the present invention also provides a compound having formula
- the compound having formula (I) is a compound having formula (lai) : and the compound having formula (II) is a compound having formula (Ilai) wherein R is methyl and X is a halogen or -OSO 2 PhR.
- the present invention also provides a compound having formula (I) obtained using any one of the processes described herein.
- the present invention also provides a compound having formula (lai) obtained using any one of the processes described herein.
- the present invention also provides a method for isolating a compound having formula (I) from a mixture comprising the compound having formula (I) , wherein the method comprises (i) preparing a multi-phase system comprising the compound having formula (I) , a water-immiscible solvent and water, and (ii) obtaining and isolating solids of the compound having formula (I) from the multiphase system.
- the water is added in the form of an aqueous basic solution.
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH 4 OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w/w) .
- the multi-phase system is a mixture comprising a liquid and solids, wherein the method comprises filtering the solids. Preferred embodiments are described in route 1 below.
- the multi-phase system comprises an organic phase and a water phase
- the method comprises separating the organic phase from the water phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals. Preferred embodiments are described in route 2 below.
- the multi-phase system is a slurry mixture comprising solids, and the method comprises filtering the solids. Preferred embodiments are described in route 3 below.
- the compound having formula (I) is a compound having formula (lai) :
- the methods for isolating a compound having formula (I) may be applied to any mixture comprising the compound having formula (I) , including the reaction mixtures of the processes described herein for preparing the compound having formula (I) and the reaction mixtures of the processes described in PCT International Application Publication Nos. WO 2015/103142, WO 2015/103144, and WO/2021/181274 for preparing the compound having formula (I) .
- the mixture including reaction mixture resulting from the alkylation step of the process for preparing the compound having formula (I) , may comprise a non-salt form of the compound having the formula (I) , a salt form of the compound having the formula (I) , or a mixture thereof.
- the step after reacting compound having formula (II) with DMS to give the salt and/or non-salt form of the compound having the formula (I) is defined as the isolation step.
- a salt form of the compound having formula (I) is formed prior to the isolation step.
- a non-salt form of the compound having formula (I) is formed prior to the isolation step.
- the non-salt form of compound having formula (I) is obtained by adding water after reaction with DMS with compound having formula (II) .
- isolation includes neutralization of the salt form of the compound having the formula (I) .
- the present invention also provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) adding at least one water immiscible solvent and an aqueous basic solution to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids .
- the compound having formula (I) is a compound having formula (lai) :
- the compound having formula (I) in the mixture is in salt form.
- the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is polar.
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent is an organic polar solvent.
- the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.
- the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM and any combination thereof.
- the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.
- the method comprises evaporation of the polar solvent prior to filtration. In some embodiments, the method comprises partial evaporation of the polar solvent prior to filtration .
- the method comprises cooling the reaction mixture prior to filtration.
- the method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015/103144 and W02015/103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application No. PCT/IB2020/058893.
- the entire content of each of W02015/103144, W02015/103142 , and PCT/IB2020/058893 is hereby incorporated by reference.
- the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.
- the compound having formula (I) is a compound having formula (lai) :
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH 4 OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w/w) .
- the compound having the formula (I) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution. In some embodiments, the compound having the formula (I) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.
- the water immiscible solvent is polar. In some embodiments, the water immiscible solvent is non-polar. In some embodiments, the water immiscible solvent is an organic polar solvent .
- the water immiscible solvent includes but not limited to CPME, MeTHF, DCM, toluene, anisole or any combination thereof .
- the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof.
- the water immiscible solvent is selected from the group consisting of methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , toluene, anisole, and any mixture thereof .
- the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.
- the compound having the formula (I) is crystalized from the organic phase. In some embodiments, the compound having the formula (I) is crystallized by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized by adding an anti-solvent. In some embodiments, the compound having the formula (I) is crystallized by seeding.
- the present invention provides a method for isolating a compound having the formula (I) comprising (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w/w of aqueous basic solution, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid .
- the compound having formula (I) in the mixture is in salt form.
- the present invention provides a method for isolating the compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w/w of aqueous basic solution, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.
- the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.
- the organic polar solvent is an organic polar water immiscible solvent.
- organic water immiscible solvent has a dielectric constant less than 20.
- organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.
- the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM and any combination thereof.
- the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .
- the organic polar solvent is DMA. In some embodiments, the organic polar solvent is CPME. In some embodiments, the organic polar solvent is MeTHF.
- the compound having formula (I) is a compound having formula (la) wherein R is alkyl.
- the compound having formula (la) is a compound having formula (lai) wherein R is methyl.
- the organic phase is cooled prior to and/or during the filtration. In some embodiments, the organic phase is cooled to 0-5°C.
- the organic polar solvent is added after the reaction to obtain the compound having the formula (I) .
- the CPME is added after the reaction to obtain the compound having the formula (I) .
- a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) .
- a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .
- the compound having the formula (I) in the mixture before the isolation step is in salt form.
- the non-polar solvent is a non-polar water immiscible solvent.
- the non-polar water immiscible solvent dissolves the compound of formula (I) .
- the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.
- the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.
- an anti-solvent is further added.
- the anti-solvent is added parallel to the to the water immiscible solvent.
- the anti-solvent is added dropwise.
- the crystallization is conducted at temperature less than 0°C.
- the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane.
- the mixture of solvent and anti-solvent are anisole and hexane.
- the mixture of solvent and anti-solvent are toluene and hexane .
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO3, Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO3, Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of K2CO3.
- the compound having formula (I) is a compound having formula (la) wherein R is alkyl.
- the compound having formula (la) is a compound having formula (lai) wherein R is methyl.
- the organic phase is cooled prior to and/or during the filtration. In some embodiments, the organic phase is cooled to 0-5°C.
- the crystallization is done by concentration of the solvent.
- the crystallization is done with crystal seeding .
- the mixture is seeded with 0.1-1% of the compound of formula (I) .
- the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) .
- anisole and hexane are added after the reaction to obtain the compound having the formula (I) .
- a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) .
- a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •
- the method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015/103144 and W02015/103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application No. PCT/IB2020/058893.
- the entire content of each of W02015/103144, W02015/103142 , and PCT/IB2020/058893 is hereby incorporated by reference.
- the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, and at least one solvent wherein the method comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.
- the compound having formula (I) is a compound having formula (lai) :
- the method includes adding additional solvent.
- the aqueous basic solution comprises DABCO, TBAB, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt or any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , Et 3 N, NaOMe, NaOEt and any combination thereof.
- the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 NH 4 OH, NaOH, and any combination thereof.
- the aqueous basic solution is an aqueous solution of K 2 CO 3 .
- the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w/w) .
- the compound having the formula (I) in the mixture is in salt form.
- the mixture comprises a solvent. In some embodiments, the slurry mixture comprises a solvent.
- the mixture comprising the compound having formula (I) may comprise
- the additional solvent is a solvent used to isolate or assist in the isolation of the compound having formula (I) .
- the additional solvent may be added directly to the mixture.
- the additional solvent may also be added with the aqueous basic solution.
- the additional solvent is the same as the solvent (s) used during the process for preparing the compound having formula (I) .
- the additional solvent is different from the solvent (s) used during the process for preparing the compound having formula (I) .
- the additional solvent is a polar solvent.
- the additional solvent is a water immiscible solvent.
- the polar solvent has a dielectric constant equal to or above 4. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.
- the ratio between the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is about 1:1.
- the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.
- the additional solvent is a polar solvent and the polar solvent is CPME .
- the solvent used during the process for preparing the compound having formula (I) is DMA and the additional solvent is CPME.
- the ratio between CPME to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (I) is about 1:1.
- the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.
- the slurry mixture is mixed for 30 minutes to 8 hours . In some embodiments, the slurry mixture is mixed at temperature between 25 to 60 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 50 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 35 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 30 degrees Celsius.
- the slurry mixture is mixed using mechanical stirrer .
- the slurry mixture is mixed using high shear stirrer .
- the slurry mixture is mixed using both mechanical stirrer and high shear stirrer.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution.
- the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution.
- the precipitated solids are filtered at a temperature between 15 to 45 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 15 to 20 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 20 to 25 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 25 to 30 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 30 to 35 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 35 to 40 degrees Celsius. In some embodiments, in step (2) , the precipitated solids are filtered at a temperature between 40 to 45 degrees Celsius.
- the filtered solid obtained in step (2) is washed with an organic solvent during filtration in step (2) .
- the organic solvent is CPME.
- the filtered solid obtained in step (2) is washed with water during filtration in step (2) .
- the filtered solid is mixed with water and stirred for 1 to 3 hours and filtered.
- the filtered solid is mixed with water and stirred at a temperature of 25-50 degrees Celsius and filtered.
- the organic solvent is the same organic solvent as used in obtaining the compound having formula (I) .
- the aqueous basic solution is 15% of K2CO3 in water based on the total weight (w/w) of K2CO3 in water.
- the organic phase is the solution which is obtained in the reaction of compound having the formula (II) with DMS .
- the organic phase is obtained by adding an organic water immiscible solvent to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.
- the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) .
- PTC phase transfer catalyst
- TBAB tetra-n-butylammonium bromide
- a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) in weight ratio of 10:1 prior to washing with 2-18% w/w of aqueous basic solution.
- the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to 65°C prior to washing with 2-18% w/w of aqueous basic solution.
- the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to about 50°C prior to washing with 2-18% w/w of aqueous basic solution.
- the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved in CPME.
- the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved with CPME and washed with water base solution.
- the resultant mixture is a mixture of the compound having formula (I) with the solvent which was used in the reaction of the compound having formula (II) with DMS.
- the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one to 5-fluoro- 4-imino-3-methyl-l- (toluene-4-sulfonyl ) -3, 4-dihydro-lH-pyrimidin- 2-one is higher than 50%.
- the chemical yield of 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%.
- the yield of the purified 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.
- the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one to 5-fluoro- 4 -imino- 3 -methyl-1- (phenyl- 4 -sulf onyl ) -3 , 4 -di hydro- IH-pyrimi di n- 2-one is higher than 50%.
- the chemical yield of 5-f luoro-4-imino-3- methyl-1- (phenyl-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%.
- the yield of the purified 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.
- the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) at least one water immiscible solvent, and at least one additional solvent, wherein the method comprises (i) washing the mixture with water to obtain slurry mixture containing solids, and (ii) filtering the precipitated solids.
- the method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015/103144 and W02015/103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application No. PCT/IB2020/058893.
- the entire content of each of W02015/103144, W02015/103142 , and PCT/IB2020/058893 is hereby incorporated by reference.
- the present invention also provides a compound having formula (I) prepared using the process described herein.
- the present invention also provides a compound having formula (lai) prepared using the process described herein.
- reaction conditions sufficient to produce the desired compound.
- Such conditions e.g. temperature, time, molarity, etc., may be varied by one of ordinary skill in the art based on the methods and protocols described herein.
- the present invention also provides a method for crystallizing or recrystallizing a compound having formula (I) , comprising (i) preparing a solution comprising a compound having formula (I) and a solvent, and (ii) contacting the solution with an anti-solvent.
- the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane.
- the solvent is one where the anti-solvent can be dissolved in.
- the method for crystallizing or recrystallizing a compound having formula (I) described herein may be used for crystallizing or recrystallizing the compound having formula (I) prepared using any process, including but not limited to the processes described herein and in PCT International Application Publication Nos. WO 2015/103142, WO 2015/103144, WO/2021/ 059160 , and WO/2021/ 181274 , the entire content of each of which is hereby incorporated by reference .
- the method comprises preparing the compound having formula (I) and crystallizing or recrystallizing the compound having formula (I) comprising (i) preparing a solution comprising the compound having formula (I) and a solvent, and (ii) contacting the solution with an anti-solvent.
- the compound of having formula (I) may be prepared using any process, including but not limited to the processes described herein and in PCT International Application Publication Nos. WO 2015/103142, WO 2015/103144, WO/2021/059160 and WO/2021/181274, the entire content of each of which is hereby incorporated by reference .
- the present invention also provides use of an anti-solvent to crystalize or recrystallize a compound having formula (I) from a solution thereof.
- the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane.
- the compound having formula (I) is in a reaction mixture resulting from preparing the compound having formula (I) using any one of the processes described herein or any one of the processes described in PCT International Application Publication Nos. WO 2015/103142, WO 2015/103144, WO/2021/059160 and WO/2021/181274, the entire content of each of which is hereby incorporated by reference.
- the present invention also provides a method for isolating a compound having formula (II) from a mixture comprising the compound having formula (II) , wherein the method comprises (i) adding a protic solvent to the mixture to precipitate the compound having formula (II) from the mixture, and (ii) collecting the precipitated compound of formula (II) .
- the protic solvent is water, methanol, or a combination thereof.
- the methods for isolating a compound having formula (II) may be applied to any mixture comprising the compound having formula (II) , including the reaction mixtures of the processes described herein for preparing the compound having formula (II) and the reaction mixtures of the processes described in PCT International Application Publication Nos. WO 2015/103142, WO 2015/103144, and WO/2021/181274 for preparing the compound having formula (II) , the entire content of each of which is hereby incorporated by reference .
- Example 1 reacting 5-f luorocytosine with compound having the formula (III) in DMA and water and K2CO3 as base.
- 5-f luorocytosine (99%, 80.1 gr) was added to IL glass reactor that contains 200 gr of water and 200 gr of DMA.
- K2CO3 solid, 114.9 gr, 1.35 mol equiv.
- Tosyl chloride (128 gr, 1.05 mol equiv.) was added in one portion at 0°C and the solution was mixed at temperature of 0°C to 5°C.
- the reaction was monitored using HPLC and then 200 gr of water were added and the temperature was heated to 25°C and mixed for 2 hours.
- the obtained solid was filtered off using Buchner funnel.
- the cake was washed with water and dried in vacuum oven at 55 to 65°C. 178 gr of desired product were obtained in purity of 90.9% and yield of 93% .
- the product contains impurity A (2.4%) and impurity B (0.2%) .
- Example 2 reacting 5-f luorocytosine with compound having the formula (III) in DMA and EtsN as base
- Example 3 reacting 5-f luorocytosine with compound having the formula (III) in DMA and water and K2CO3 as base
- Example 4 (b) reacting 5-f luorocytosine with compound having the formula (III) in ACN and EtsN as base
- Example 4 (c) reacting 5-f luorocytosine with compound having the formula (III) in MeCN and NEts
- 5-f luorocytosine (99%, 5 gr) was added to a round bottom flask that contained 15 gr of acetonitrile.
- Triethylamine (4.6 gr, 1.2 mol equiv. ) was added and the flask was cooled to 5 °C.
- Tosyl chloride (8 gr, 1.1 mol equiv.) was added in one portion at 5°C and the solution was mixed at a temperature of 5°C. The reaction was monitored using HPLC and then methanol was added and the temperature was heated to 25°C and mixed for 2 hours. The obtained solid was filtered off using Buchner funnel. 9 gr of desired product was obtained in purity of 74% and yield of 61%.
- the product contains impurity A (0.5%) and impurity B (0.3%) .
- Example 5 reacting 5-f luorocytosine with compound having the formula (III) in water and DMA and DMAP as base
- the product was obtained in purity of 79.6% and contains impurity
- Example 6 reacting 5-f luorocytosine with compound having the formula (III) in MeCN and triethylamine as base
- Example 8 reacting 5-f luorocytosine with compound having the formula (ITT) in DMA and sodium carbonate as base
- Example 9 reacting 5-f luorocytosine with compound having the formula (ITT) in DMBA and sodium carbonate as base
- Example 10 reacting 5-f luorocytosine with compound having the formula (ITT) in water and DMAP as base
- Example 11 reacting 5-f luorocytosine with compound having the formula (III) in DMA, water and DMBA and potassium hydroxide as base
- Example 12 reacting 5-f luorocytosine with compound having the formula (III) in DMA, water and DMBA and sodium hydroxide as base
- Example 13 reacting 5-f luorocytosine with compound having the formula (III) in DMA and water and K2CO3 as base.
- 5-f luorocytosine (99%, 120 gr) was added to IL glass reactor that contains 360 gr water and 160 gr of DMA.
- K2CO3 204 gr, 1.6 mol equiv.
- Tosyl chloride (192 gr, 1.05 mol equiv.) was added in one portion at -5°C to -3°C over 1.5 hours and the solution was mixed at temperature of -5°C for 3.5 hours.
- the reaction was monitored using HPLC . 93% selectivity was observed.
- the reaction was heated to 15 °C and the product was filtered off and dried in vacuum oven at 55 °C. 329 gr of product in purity of 60% was obtained.
- the isolated yield was 76% .
- Example 14 reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in absence of base in CPME and DMA
- the phases were separated and the organic phase was mixed with another 5 kg solution of 10% K2CO3 containing 85 gr of TBAB for 1 hour followed by phase separation and repeating the same procedure again.
- the organic phase was washed with 9 kg of water and then 10 kg of CPME was evaporated at 100 mbar at 50°C.
- Example 15(a) Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in CPME and DMA and in the presence of TBAB.
- Example 15(b) Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in DMA and in the presence of NaOMe.
- Example 16 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in absence of base in CPME and DMA 1:1
- Example 17 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in absence of base in DMA
- the mixture was cooled to 0-5°C over 1 hour and the obtained solid was filtered off using Buchner funnel.
- the cake was mixed with 300 gr water for 1 hour at 40°C, cooled to 0°C, filtered and the process of water slurry repeated again.
- the product was dried in vacuum oven at 65°C. The product was obtained in 80% isolated yield in 99% purity .
- Example 18 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) 5 equiv. in absence of base in DMA and CPME.
- the phases were separated and the organic phase was mixed with another 176 gr solution of 10% containing 0.5 gr of TBAB for 1 hour followed by phase separation and repeating the same procedure again.
- the organic phase was washed with 300 gr of water and then 300 gr of CPME was evaporated at 100 mbar at 50 °C.
- Example 19 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in presence of base in DMA and CPME.
- Example 20 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in presence of base in DMA and CPME.
- Example 21 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in high shear stirring in DMA/CPME.
- Example 22 Reaction of compound having the formula (Hai) with dimethylsulphate (DMS) in DMA and CPME.
- the mixture was cooled to 30°C and the mixture was stirred for 6 hours followed by cooling to 0°C over 15 minutes.
- the product was filtered using buchner funnel and the cake was washed with 200 gr water and dried at 65°C overnight in vacuum oven. The product was obtained in 98.1% purity and 60% yield.
- Example 23 Reaction of compound having the formula (Hai) with dimethylsulphate (DMS) in DMA and CPME.
- the product was filtered using buchner funnel and the cake was washed with 150 gr water and filtered, the wet cake was mixed with 700 gr of water for 3 hours, filtered and washed with 150 gr water, filtered and dried in vacuum oven at 65 °C.
- the product was obtained in 97% purity and 65% yield.
- Example 24 Reaction of compound having the formula (Hai) with dimethylsulphate (DMS) in CPME at 85°.
- Example 25 Reaction of compound having the formula (Hai) with dimethylsulphate (DMS) in CPME/DMA at 25°C.
- Example 28 Reaction of compound having the formula (Ilai) with dimethylsulphate (DMS) in DMA and anisole.
- the reactor mixture was heated to 60 °c.
- This mixture was mixed for 30min at 30 °c then cooled to 0°c during 3 hr .
- the reaction mixture was stirred O.N and filtered.
- the claimed process is an improvement over the processes described in W02015 / 103144 and/or W02015 / 103142 for synthesi zing 5- ( fluoro- 4 -imino -3 -methyl ) -l-tosyl-3 , 4 -di hydro-pyrimidine— ( Ih) -one .
- the present invention provides an efficient pathway for synthesis of compound I with two step reaction wherein each step is one step reaction without additional protection group and/or without using the alkylation reaction as described in W02015/ 103144 and/or W02015 / 103142 .
- the process is designed to solve the problem of non-selective sulfonation and alkylation steps as described in the previous process .
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Abstract
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CN202280062142.3A CN118139845A (zh) | 2021-09-15 | 2022-09-15 | 用于制备5-氟-4-亚氨基-3-甲基-1-(甲苯-4-磺酰基)-3,4-二氢-1h-嘧啶-2-酮的方法 |
EP22783569.1A EP4402131A1 (fr) | 2021-09-15 | 2022-09-15 | Procédé de préparation de 5-fluoro-4-imino-3-méthyl-1-(toluène-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one |
IL311455A IL311455A (en) | 2021-09-15 | 2022-09-15 | Method for preparing 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-H1-pyrimidin-2-one |
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Citations (6)
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WO2011137002A1 (fr) * | 2010-04-26 | 2011-11-03 | Dow Agrosciences Llc | Dérivés n3-substitué-n1-sulfonyl-5-fluoropyrimidinone |
WO2013025795A1 (fr) * | 2011-08-17 | 2013-02-21 | Dow Agrosciences Llc | Dérivés de 5-fluoro-4-imino-3-(substitué)-3,4-dihydropyrimidin-2-(1h)-one |
WO2015103144A1 (fr) | 2013-12-31 | 2015-07-09 | Dow Agrosciences Llc | 5-fluoro -4-imino -3- (alkyle/alkyle substitué) -1- (arylsulfonyl) -3,4-dihydropyrimidin -2(1h)-one et procédés pour leur préparation |
WO2020058893A1 (fr) | 2018-09-19 | 2020-03-26 | Beijing Bytedance Network Technology Co., Ltd. | Prédicteur de vecteur de mouvement basé sur un historique, pour une copie intra-bloc |
WO2021059160A1 (fr) | 2019-09-23 | 2021-04-01 | Adama Makhteshim Ltd. | Procédé de préparation de 5-(fluoro-4-imino-3-méthyl)-1-tosyl-3,4-dihydropyrimidine-(1h)-one |
WO2021181274A1 (fr) | 2020-03-09 | 2021-09-16 | Adama Makhteshim Ltd. | Procédé de préparation de 5-fluoro-4-imino-3-méthyl-1-(toluène-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one |
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- 2022-09-15 WO PCT/IB2022/058732 patent/WO2023042126A1/fr active Application Filing
- 2022-09-15 EP EP22783569.1A patent/EP4402131A1/fr active Pending
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WO2011137002A1 (fr) * | 2010-04-26 | 2011-11-03 | Dow Agrosciences Llc | Dérivés n3-substitué-n1-sulfonyl-5-fluoropyrimidinone |
WO2013025795A1 (fr) * | 2011-08-17 | 2013-02-21 | Dow Agrosciences Llc | Dérivés de 5-fluoro-4-imino-3-(substitué)-3,4-dihydropyrimidin-2-(1h)-one |
WO2015103144A1 (fr) | 2013-12-31 | 2015-07-09 | Dow Agrosciences Llc | 5-fluoro -4-imino -3- (alkyle/alkyle substitué) -1- (arylsulfonyl) -3,4-dihydropyrimidin -2(1h)-one et procédés pour leur préparation |
WO2015103142A1 (fr) | 2013-12-31 | 2015-07-09 | Dow Agrosciences Llc | 5-fluoro-4-imino-3-(alkyle/alkyle substitue)-1- (arylsulfonyl)-3,4-dihydropyrimidin-2(1h)-one et leurs procedes de preparation |
WO2020058893A1 (fr) | 2018-09-19 | 2020-03-26 | Beijing Bytedance Network Technology Co., Ltd. | Prédicteur de vecteur de mouvement basé sur un historique, pour une copie intra-bloc |
WO2021059160A1 (fr) | 2019-09-23 | 2021-04-01 | Adama Makhteshim Ltd. | Procédé de préparation de 5-(fluoro-4-imino-3-méthyl)-1-tosyl-3,4-dihydropyrimidine-(1h)-one |
WO2021181274A1 (fr) | 2020-03-09 | 2021-09-16 | Adama Makhteshim Ltd. | Procédé de préparation de 5-fluoro-4-imino-3-méthyl-1-(toluène-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one |
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LIAQAT ET AL.: "Supporting Information: RNA-Cleaving Deoxyribozymes Differentiate Methylated Cytidine Isomers in RNA", ANGEW. CHEM. INT. ED., 29 June 2021 (2021-06-29), pages 1 - 25, XP055982996, ISSN: 1433-7851, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fanie.202106517&file=anie202106517-sup-0001-misc_information.pdf> DOI: 10.1002/anie.202106517 * |
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CN118139845A (zh) | 2024-06-04 |
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